The specific goal of this application is to identify and characterize the molecular events leading to elastic fiber alterations and calcification in pseudoxanthoma elasticum (PXE) as a pertinent disease model to better understand the dynamics governing the super-assembly and homeostasis of elastic fibers. These are large, complex molecules that provide mechanical properties to elastic tissues and regulate cell fate in many developing tissues. These fibers are essential for the development of life but how they are assembled and maintained is not fully understood. Pseudoxanthoma elasticum (PXE) is a heritable disease characterized by elastic fiber fragmentation and calcification. PXE was long thought to be a prototypic connective tissue disease but the PXE phenotype was unexpectedly linked to a gene (ABCC6) apparently unrelated to elastic fibers. We have obtained preliminary results showing that circulating factors from PXE patient sera altered elastic fibers formation in vitro. This data suggested that PXE is a metabolic disorder with secondary extracellular matrix remodeling and that circulating factors might either participate in or exacerbate the development of the disease phenotype. Hence, we hypothesize that abnormal circulating factor(s) arise in the blood as a secondary consequence of ABCC6 failure to export its substrate(s);these PXE factor(s) then percolate from the circulation into the connective tissue and either preclude the initial deposition of elastic fibers or promote structural alterations that ultimately result in their calcification. To test this hypothesis, we propose to undertake two specific aims corresponding to (i) the molecular characterization of elastic fiber defects induced by the presence of serum from PXE patients in culture of dermal fibroblasts (ii) the identification of the serum factor(s) responsible for the these defects. We expect that our proposed experiments will lead to the identification of factor(s) interfering with elastic fiber and the possible development of therapeutic measures alleviating the symptoms of PXE. We also anticipate from our studies a new level of understanding of elastic fiber formation and aging in vascular tissues.

Public Health Relevance

Elastic fibers are large, complex molecules that are important for life by providing specific mechanical properties to elastic tissues. To understand how elastic fibers are maintained over time, we are exploring the pathologic mechanism underlying pseudoxanthoma elasticum, a heritable disease, characterized by progressive elastic fiber fragmentation and calcification.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL087289-01A2
Application #
7740288
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Srinivas, Pothur R
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$187,500
Indirect Cost
Name
University of Hawaii
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
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Le Saux, Olivier; Fulop, Krisztina; Yamaguchi, Yukiko et al. (2011) Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver. PLoS One 6:e24738
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